Mucin-1 (Mucin1, also described as MUC1 hereinafter), which is one kind of mucin, is a tumor-associated antigen; and MUC1 is a high molecular weight glycoprotein which is expressed by many adenocarcinomas. It is known that the extracellular domain, which is essential to the protein, of the membrane glycoprotein is mainly composed of 30 to 90 tandem-type repeats of a core sequence of 20 amino acids (also referred to as “Tn20-mer” hereinafter in the present description; HGVTSAPDTRPAPGSTAPPA (SEQ ID No.: 1)) rich in serine, threonine and proline. The repetition number of the “Tn20-mer” expressed is different depending on the individual pieces. The repetition number is genetically determined, resulting in size polymorphisms.
Tumor MUC1 generally has low glycosylation, and comprises one or more glycosylation sites frequently with abnormal sugar chain extension. This abnormal glycosylation generates the result of exposure of a normal cryptic peptide epitope and the creation of a novel carbohydrate epitope. Due to their high molecular weight (2×105 to 5×107 daltons) and extensive glycosylation, a cellular membrane mucin is present as a soft rod, and protrudes from a cellular surface at a relatively large distance. Therefore, the mucin forms an important component of the polysaccharide coat, and is probably the first point of cellular contact between an antibody and an immune system cell.
A large number of monoclonal antibodies (MAb) to purified MUC1 and to synthetic peptides and glycopeptides derived from MUC1 have been previously produced (Patent Documents 1 to 5 and Non-Patent Documents 1 and 2). Most of the minimum sequence recognition of these antibodies are thought to be present within APDTRPAP (SEQ ID NO: 10). The sequence SAPDTRP (SEQ ID NO: 11) in a MUC1 tandem-type repetition is an immunodominant B cell epitope, and the sequence PDTRP (SEQ ID NO: 12) is positioned at a T-cell epitope of tandem-type repetition. Since the threonine included in these sequences is heavily O-glycosylated, the threonine is thought to affect the selectivity of antibodies binding to MUC1 and the affinity thereof. However, while the monoclonal antibodies described above were able to recognize the difference in the peptides, which are epitopes, by the presence or absence of the glycosylation, none of the monoclonal antibodies were able to recognize the difference in the sugar chain structures. Thus, it was not possible to say that the selectivity to cancer cells was sufficient.